Endothelial dysfunction in cerebral microcirculation during hypothermic cardiopulmonary bypass in newborn lambs

OBJECTIVES: Inflammatory stimuli or mechanical stresses associated with hypothermic cardiopulmonary bypass could potentially impair cerebrovascular function, resulting in inadequate cerebral perfusion. We hypothesize that hypothermic cardiopulmonary bypass is associated with endothelial or vascular smooth muscle dysfunction and associated cerebral hypoperfusion. Therefore we studied the cerebrovascular response to endothelium-dependent vasodilator, acetylcholine, endothelium-independent nitric oxide donor, sodium nitroprusside, and vasoactive amine, serotonin, in newborn lambs undergoing hypothermic cardiopulmonary bypass (nasopharygeal temperature = 18 degrees C). METHODS: Studies were performed on 13 newborn lambs equipped with a closed cranial window, allowing for direct visualization of surface pial arterioles. Six animals were studied while undergoing hypothermic cardiopulmonary bypass, whereas seven served as nonbypass, warm (37 degrees C) controls. Pial arteriolar caliber (range = 111 to 316 microm diameter) was monitored using video microscopy. RESULTS: Topical application of acetylcholine caused a dose-dependent increase in arteriolar diameter in the control group that was absent in animals undergoing hypothermic cardiopulmonary bypass. Hypothermic cardiopulmonary bypass did not alter the vasodilation in response to sodium nitroprusside. Furthermore, the contractile response to serotonin was fully expressed during hypothermic cardiopulmonary bypass. CONCLUSIONS: The specific loss of acetylcholine-induced vasodilation suggests endothelial cell dysfunction rather than impaired ability of vascular smooth muscle to respond to nitric oxide. It is speculated that loss of endothelium-dependent regulatory factors in the cerebral microcirculation during hypothermic cardiopulmonary bypass may enhance vasoconstriction, and impaired cerebrovascular function may be a basis for associated neurologic injury during or after hypothermic cardiopulmonary bypass.     

Effects of cardiopulmonary bypass and circulatory arrest on endothelium-dependent vasodilation in the lung

Endothelial injury with failure of pulmonary endothelium-dependent vasodilatation has been proposed as a possible cause for the increased pulmonary vascular resistance observed after cardiopulmonary bypass, but the mechanisms underlying this response are not understood. An in vivo piglet model was used to investigate the role of endothelium-dependent vasodilatation in postbypass pulmonary hypertension. The pulmonary vascular responses to acetylcholine, a receptor-mediated endothelium-dependent vasodilator, and nitric oxide, an endothelium-independent vasodilator, were studied in one group of animals after preconstriction with the thromboxane A2 analog U46619 (n = 6); a second group was studied after bypass with 30 minutes of deep hypothermic circulatory arrest (n = 6). After preconstriction with U46619, both acetylcholine and nitric oxide caused significant decreases in pulmonary vascular resistance (34% +/- 6% decrease, p = 0.007, and 39% +/- 4% decrease, p = 0.001). After cardiopulmonary bypass with circulatory arrest, acetylcholine did not significantly change pulmonary vascular resistance (0% +/- 8% decrease, p = 1.0), whereas nitric oxide produced a 32% +/- 4% decrease in pulmonary vascular resistance (p = 0.007). These results demonstrate a loss of receptor-mediated endothelium-dependent vasodilatation with normal vascular smooth muscle function after circulatory arrest. Administration of the nitric oxide synthase blocker Ngamma-nitro-L-arginine-methyl-ester after circulatory arrest significantly increased pulmonary vascular resistance; thus, although endothelial cell production of nitric oxide may be diminished, it continues to be a major contributor to pulmonary vasomotor tone after cardiopulmonary bypass with deep hypothermic circulatory arrest. In summary, cardiopulmonary bypass with deep hypothermic circulatory arrest results in selective pulmonary endothelial cell dysfunction with loss of receptor-mediated endothelium-dependent vasodilatation despite preserved ability of the endothelium to produce nitric oxide and intact vascular smooth muscle function.     

Constitutive nitric oxide synthase is expressed and nitric oxide-mediated relaxation is preserved in retrieved human aortocoronary vein grafts

Although little is known about the endothelial cell function of human saphenous vein coronary artery bypass grafts, there is evidence to suggest that receptor-activated, endothelial-dependent relaxation mediated by nitric oxide is impaired. This study examines the expression and function of endothelial cell constitutive nitric oxide synthase (cNOS) of aortocoronary vein bypass grafts and human saphenous veins obtained from 10 patients undergoing repeat coronary artery bypass grafting for recurrent ischemic symptoms. Following precontraction with norepinephrine (10(-5) M), responses to acetylcholine (receptor-mediated, endothelium-dependent), calcium ionophore (A23187; receptor-independent, endothelium-dependent), and sodium nitroprusside (endothelium-independent) were assessed. Following total RNA extraction using phenol/guanidinium isothiocyanate from specimens of human saphenous vein and vein graft, a quantitative RNase Protection Assay (RPA) was performed using a cRNA riboprobe corresponding to a fragment of the human endothelial cell cNOS gene. Histologically, the vein grafts showed both intimal hyperplasia development and focal atherosclerosis formation compared to the saphenous veins. Scanning electron microscopy of the saphenous veins and the vein grafts showed an intact endothelium. Precontracted vein grafts did not relax in response to acetylcholine; in contrast, the saphenous vein relaxed in a dose-dependent manner to reach a maximal relaxation of 19 +/- 4% precontracted tension. Saphenous veins and vein grafts relaxed in response to A23187 with maximal relaxation of 92 +/- 5 and 73 +/- 13%, respectively. Both vessels relaxed in a dose dependent manner to sodium nitroprusside. RPA normalized to beta-actin showed similar levels of expression of endothelial cell cNOS equivalent to 1 pg of sense RNA in both the saphenous vein and vein graft.(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic effects of dopexamine and nitric oxide synthase inhibition in healthy and endotoxaemic sheep

In endothelium-denuded guinea-pig isolated basilar artery preparations, hydroxocobalamin (30, 100 and 300 microM) concentration-dependently inhibited the vasodilator responses to exogenous nitric oxide (NO), whereas the vasodilator responses to nitrergic nerve stimulation were slightly reduced by high (100 and 300 microM) but not by the low (30 microM) concentration of hydroxocobalamin. Vasodilatation in response to sodium nitroprusside (10-100 nM) was totally abolished by 300 microM hydroxocobalamin. In endothelium-intact preparations, vasodilator responses to acetylcholine (0.3-3 microM) were significantly reduced or abolished by hydroxocobalamin (30-300 microM). The mean reduction by hydroxocobalamin of relaxations to acetylcholine was significantly greater than that of the equivalent response evoked by nitrergic nerve stimulation. The findings suggest that the nitrergic transmitter in the guinea-pig basilar artery may be quantitatively less susceptible than the endothelium-derived relaxing factor to the NO scavenger hydroxocobalamin.     

Ischemic preconditioning attenuates postischemic coronary artery endothelial dysfunction in a model of minimally invasive direct coronary artery bypass grafting

OBJECTIVE: Unmodified reperfusion without cardioplegia in minimally invasive direct coronary artery bypass grafting procedures causes endothelial dysfunction that may predispose to polymorphonuclear neutrophil-mediated myocardial injury. This study tested the hypothesis that ischemic preconditioning in a minimally invasive direct coronary artery bypass grafting model attenuates postischemic endothelial dysfunction in coronary vessels. METHODS: In anesthetized dogs, the left anterior descending coronary artery was occluded for 30 minutes and reperfused for 3 hours without ischemic preconditioning (no-ischemic preconditioning; n = 7); in 7 dogs, the left anterior descending occlusion was preceded by 5 minutes occlusion followed by 5 minutes of reperfusion. Relaxation responses to stimulators of nitric oxide synthase were used to evaluate endothelial function in arteries from the ischemic-reperfused (left anterior descending) and nonischemic (left circumflex coronary artery) zones. RESULTS: Stimulated endothelial-dependent relaxation of epicardial left anterior descending artery to incremental concentrations of acetylcholine in the no-ischemic preconditioning animals was shifted to the right, and maximal relaxation was attenuated compared with the nonischemic left circumflex coronary artery (117% +/- 4% vs 138% +/- 5%). In contrast, acetylcholine-induced maximal relaxation was comparable in the left anterior descending artery versus left circumflex coronary artery in the ischemic preconditioning group (130% +/- 6% vs 135% +/- 5%). In 150- to 200- microm left anterior descending microvessels, 50% relaxation occurred with a lower concentration (log[M]) of acetylcholine in ischemic preconditioning versus no-ischemic preconditioning (-8.0 +/- 0.4 vs -7.0 +/- 0.1) with no group differences in smooth muscle relaxation to sodium nitroprusside, suggesting endothelial-specific damage. Adherence of fluorescent labeled polymorphonuclear neutrophils to epicardial coronary artery endothelium, used as an index of basal (unstimulated) anti-polymorphonuclear neutrophil function, was significantly attenuated by ischemic preconditioning versus no-ischemic preconditioning (293 +/- 25 polymorphonuclear neutrophils/mm2 vs 528 +/- 29 polymorphonuclear neutrophils/mm2). CONCLUSION: In this minimally invasive direct coronary artery bypass grafting model, both agonist-stimulated and basal postischemic endothelial dysfunction were attenuated by ischemic preconditioning.     

Role of the endothelium in placental dysfunction after fetal cardiac bypass

BACKGROUND: Fetal cardiac bypass causes placental dysfunction, characterized by increased placental vascular resistance, decreased placental blood flow, hypoxia, and acidosis. Vasoactive factors produced by the vascular endothelium, such as nitric oxide and endothelin 1, are important regulators of placental vascular tone and may contribute to this placental dysfunction. METHODS: To investigate the role of the vascular endothelium in placental dysfunction related to fetal cardiac bypass, we studied 3 groups of fetal sheep. In the first group (n = 7) we determined placental hemodynamic responses before and after bypass to an endothelium-dependent vasodilator (acetylcholine), an endothelium-independent vasodilator (nitroprusside), and endothelin 1. In the second group (n = 8) a nonspecific endothelin receptor blocker (PD 145065) was administered and placental hemodynamic values were measured before and after bypass. In the third group (n = 5) endothelin 1 levels were measured before and after bypass. RESULTS: Before fetal cardiac bypass exogenous endothelin 1 decreased placental blood flow by 9% and increased placental resistance by 9%. After bypass endothelin 1 decreased placental flow by 47% and increased resistance by 106%. There was also a significant attenuation of the placental vascular relaxation response to acetylcholine after bypass, whereas the response to nitroprusside was not significantly altered. In fetuses that received the PD 145065, placental vascular resistance increased significantly less than in control fetuses (28% versus 62%). Similarly, placental blood flow decreased significantly more (from 6. 3 +/- 3.1 to 28.3 +/- 10.4 pg/mL; P =.01) in control fetuses than in fetuses receiving PD 145065 (33% versus 20%). Umbilical venous endothelin 1 levels increased significantly in fetuses exposed to fetal bypass but did not change in control fetuses. CONCLUSIONS: The basal endothelial regulatory mechanisms of placental vascular tone were deranged after fetal cardiac bypass. Endothelin receptor blockade, which substantially reduced postbypass placental dysfunction, and other interventions aimed at preserving endothelial function may be effective means of optimizing fetal outcome after cardiac bypass.     

Nephrotoxicity of acyclovir and ganciclovir in rats: evaluation of glomerular hemodynamics

Effects of pretreatment with thiopental on endothelium-dependent vasodilator responses elicited by drugs in rat aortic rings were investigated. The vasodilators employed were acetylcholine and histamine (endothelium- and receptor-dependent), A23187 (endothelium-dependent but receptor-independent) and sodium nitroprusside (endothelium-independent); they were tested 15 or 60 min after aortic preparations were exposed during 15 min to thiopental. Pretreatment with the barbiturate reversibly inhibited relaxation elicited by either acetylcholine and histamine, but a high concentration of the anesthetic was needed (3.1 mg/ml). On the contrary, thiopental did not modify the relaxation elicited by sodium nitroprusside or A23187. In addition, the barbiturate inhibited basal and acetylcholine-stimulated production of nitrites (an indicator of nitric oxide output) in aortic rings. In conclusion, thiopental inhibited the endothelium-dependent relaxation elicited by either acetylcholine or histamine. Although the barbiturate also inhibited nitric oxide production, the reduction in the relaxant response provoked by it does not seem to be the result of direct guanylate cyclase or nitric oxide synthase alterations, since thiopental did not modify the effect of sodium nitroprusside or A23187. Disturbances elicited by thiopental on endothelial receptors or on signal transduction elements may indirectly provoke nitric oxide synthase inhibition.     

Comparison of endothelial reactivity of infrarenal and suprarenal aortic segments in rodents

OBJECT: Human infrarenal aorta is prone to develop atherosclerotic lesions. Infrarenal aortic blood flow depends on lower limb muscular activity. Blood flow variations cause shear stress variations known to influence endothelial reactivity. The purpose of this study is to compare vascular reactivity of the suprarenal and infrarenal aorta. MATERIAL AND METHODS: Endothelium-dependent relaxation to acetylcholine (ACH) and calcium ionophore (Cal), and endothelium-independent relaxation to sodium nitroprussiate (SNP) in 3 aortic segments (thoracic, abdominal suprarenal and infrarenal) harvested from Sprague-Dawley rats (n = 12) were studied in organ chambers. RESULTS: Endothelium-dependent relaxations to ACH were similar for the 3 aortic segments. However, infrarenal aorta endothelial response to Cal was decreased compared to other segments whereas response to SNP was enhanced. Contractility to vasoconstrictor agonist (phenylephrine and KCl) was diminished compared to the suprarenal segments. CONCLUSION: Endothelial reactivity is not homogeneous throughout the rat aorta. Endothelial reactivity to Cal seems decreased in the infrarenal aorta which suggests a diminished nitric oxide synthase activity. The increased sensitivity of the infrarenal aorta to nitric oxide donor such as SNP suggests a compensatory mechanism.     

Progesterone-dependent decidualization of the human endometrium is mediated by cAMP

BACKGROUND: Behavioral stress has been proposed to contribute to the occurrence of myocardial ischemia. Objective To investigate the effect of chronic exposure to behavioral stress on the function and structure of the coronary artery of borderline hypertensive rats (BHR). DESIGN: BHR were either exposed to an air-jet stress for 2 h/day for 10 days or kept in their cage for 10 days. METHODS: After 10 days, hemodynamic measurements in conscious animals were recorded, and their hearts were removed for isolation of a left ventricular coronary artery for functional studies or for fixation by retrograde perfusion for study with scanning electron microscopy. Vascular reactivity was measured in isolated coronary arteries (approximately 250 microm) maintained at an intraluminal diameter of 40 mmHg while the intraluminal diameter was recorded continuously. RESULTS: The resting mean arterial pressure and heart rate in conscious, unrestrained BHR were not altered significantly by exposure to 10 days of 2 h/day air-jet stress. Coronary artery relaxation in response to the endothelium-dependent vasodilator acetylcholine was impaired in rats exposed to the air-jet stress compared with that in controls. An attenuated response to exogenous nitric oxide in coronary arteries from stressed BHR was confirmed by the finding of a reduced sensitivity to nitroprusside, which releases nitric oxide independently from the endothelium. However, relaxation of coronary arteries in response to isoproterenol, which acts independently from nitric oxide, was not altered. Coronary artery contraction in response to endothelin-1 and phenylephrine was not altered in vessels taken from BHR exposed to behavioral stress compared with that in vessels from control rats. Scanning electron microscopy of the endothelial surface of the septal coronary artery showed no difference between vessels from control and stressed BHR. CONCLUSION: These results indicate that behavioral stress impairs endothelium-dependent and nitric oxide-mediated coronary relaxation, but does not alter alpha1-adrenoceptor or endothelin-1-mediated contraction. By impairing coronary artery vascular relaxation, chronic exposure to behavioral stress may contribute to myocardial ischemia.     

Improved exposure of the pulmonary arteries for thromboendarterectomy

Pulmonary thromboendarterectomy is a surgical technique for treating pulmonary hypertension caused by unresolved pulmonary embolism. It has been recommended to perform this procedure under deep hypothermic circulatory arrest. Here we describe two technical modifications: (1) improved exposure to the right pulmonary artery by division of the superior caval vein and (2) thromboendarterectomy in normothermic cardiopulmonary bypass, with beating heart or electrically induced ventricular fibrillation. These modifications allow complete endarterectomy of both pulmonary arteries under normothermic conditions, thus avoiding hypothermic circulatory arrest, which results in short cardiopulmonary bypass times and reduces the morbidity and mortality of this procedure.     

Permissive effect of nitric oxide in arachidonic acid induced dilation in isolated rat arterioles

OBJECTIVE: Prostaglandins and nitric oxide play an important role in the regulation of arteriolar tone. L-Arginine analogues inhibit nitric oxide formation, but may also inhibit arachidonic-acid induced dilation. Nitric oxide was found to stimulate cyclooxygenase activity in cultured endothelial cells. Therefore, we hypothesized that the non-specific inhibition of prostaglandin-related dilation by L-arginine analogues is a consequence of the absence of nitric oxide. METHODS: To test this hypothesis, arteriolar segments from rat cremaster muscle were studied in a pressure myograph at 75 mmHg. Segments developed spontaneous tone, the diameter reduced from 179 +/- 3 to 98 +/- 3 microns (n = 41). In this condition, responses to exogenous arachidonic acid (1 microM) were recorded and compared with responses after addition of L-NNA, and addition of either SNAP, nitroprusside or 8-Br-cGMP in the presence of L-NNA. RESULTS: Inhibition of basal nitric oxide production with L-NNA (0.1 mM) reduced arachidonic acid-induced dilation (from 52 +/- 9 to 31 +/- 6 microns). In the presence of L-NNA, responses to arachidonic acid were augmented when exogenous nitric oxide was also present (SNAP, 31 +/- 6 microns vs. 75 +/- 5 microns; nitroprusside, 31 +/- 8 microns vs. 42 +/- 7 microns). Responses were not augmented with the second messenger of nitric oxide-mediated dilation 8-Br-cGMP (37 +/- 9 microns vs. 32 +/- 9 microns). CONCLUSIONS: These results indicate that nitric oxide directly increases arachidonic acid-induced dilation. Thus, the non-specific effect of L-arginine analogues can be explained by a permissive effect of nitric oxide on endothelial arachidonic acid metabolism.     

UFT and leucovorin: a review of its clinical development and therapeutic potential in the oral treatment of cancer

Different receptors mediating the release of endothelium-derived nitric oxide (EDNO) have been identified at endothelial level. In the present study we aimed to characterise, on rabbit aorta by means of pharmacological tools, the generation of EDNO by receptors located on endothelial cell membrane (M3, P2u, P2y) and by direct activation of Ca2+ entry into the endothelial cell. Four vasodilating drugs were tested (acetylcholine, UTP, A23187 and 2-methyl-thio-ATP); they were active only if the endothelial layer was intact, suggesting that they act through endothelial receptors. The effect of different nitric oxide synthase (NOS) inhibitors (0.1 mM: L- and D-NAME, L-NMMA, L-NIO and 7-NI) was investigated on NO-mediated relaxation induced by the relaxants in vessels with intact endothelium. NOS inhibitors differently affected relaxation mediated by the vasoactive drugs in isolated rabbit aorta. Reversibility of the inhibition by using a fixed concentration of L-arginine (0.1 mM) was different depending on the relaxing drug and NOS-inhibitor. The data obtained support the coexistence in aortic vessel of more than one endothelial cell NOS isoform, each provided with different receptor coupling.     

Lack of nitric oxide contributes to vasospasm during ischemia/reperfusion injury

Vasospasm can be a complication after free tissue transfer and replant operations. Recent studies suggest that vasospasm may be due to endothelium dysfunction, resulting in impairment of nitric oxide production. The present experiment was designed to investigate acute responses of the microcirculation of skeletal muscle to local interarterial infusion of sodium nitroprusside (a direct donor of nitric oxide and thus an endothelium-independent vasodilator) or acetylcholine chloride (which stimulates endothelium release of endogenous nitric oxide) during reperfusion after 4 hours of warm ischemia. Male Sprague-Dawley rats, each weighing 100 to 120 gm, were anesthetized with sodium pentobarbitone and were surgically prepared with vascular isolated and denervated cremaster muscles that were subjected to 4 hours warm ischemia and 2 hours of reperfusion. Sodium nitroprusside (10(-3) M), acetylcholine chloride (10(-4) M), or normal saline (eight rats for each group) were administered by local infusion (0.1 ml/hour) through the femoral artery into the natural blood flow of the cremaster. The arterial tree in the cremaster was observed and arteriole diameters (A1-A4) were measured using intravital microscopy. The number of arteriole branches having temporary stoppage of flow were counted in each cremaster. The results from this study show that local infusion of sodium nitroprusside, but not acetylcholine chloride, prevents ischemia/reperfusion vasoconstriction in A3 and A4 arterioles and thus improves microvascular blood flow. Generalized vasoconstriction caused by topically applied norepinephrine (10(-6) M) to sham ischemia cremasters could be completely reversed by the local infusion of 10(-4) M acetylcholine chloride. These results indicate that vasospasm after ischemia/reperfusion may be related to temporary endothelial cell dysfunction, resulting in the inability to produce sufficient nitric oxide during early reperfusion. Vascular smooth muscle, however, is responsive to locally administered sodium nitroprusside infusion (which is thought to provide exogenous nitric oxide).     

Effects of en bloc esophagectomy on nutritional and immune status in patients with esophageal carcinoma

We tested the hypothesis that extravascular adenosine induces the release of vasodilatory products from endothelial cells lining skeletal muscle vessels. Endothelium-intact (n = 35) and -denuded (n = 5) dog semitendinosus intramuscular arteries were isolated, cannulated, and placed in 100-mL baths containing Krebs-Henseleit bicarbonate buffer (Krebs) at 37 degrees C and gassed with 95% O2--5% CO2. Each vessel, as well as a parallel tubing segment (avascular control), was perfused at 3.5 +/- 0.2 mL/min (inflow pressure 94 +/- 2 mmHg; 1 mmHg = 133.3 Pa) with Krebs containing 100 microM phenylephrine, 6% dextran, and 15 units/mL superoxide dismutase. Perfusate from all segments dripped onto endothelium-denuded dog femoral artery rings. The addition of 10 microM acetylcholine to the perfusate to test the functional integrity of endothelium-intact donor segments did not alter resistance in vessel segments or change force in rings. The addition of 100 microM adenosine to the extravascular bath decreased resistance 1.5 +/- 0.4 mmHg.mL-1.min-1 in vessel segments but was without effect on downstream rings. When acetylcholine was retested in the presence of extravascular adenosine, a relaxation (16 +/- 6%) occurred in rings receiving perfusate from endothelium-intact segments but not endothelium-denuded or tubing segments. This relaxation was eliminated by N omega-nitro-L-arginine (10 microM), a nitric oxide synthase inhibitor, and was attenuated to 4 +/- 1% by 8-phenyltheophylline (10 microM), an adenosine receptor antagonist. Thus adenosine, in conjunction with acetylcholine, acting through a receptor-mediated event, resulted in the release of nitric oxide from the endothelium of perfused intramuscular arteries, indicating the potential for extravascular conditions to influence the release of endothelium-derived products.     

Impaired endothelium-dependent relaxation in isolated resistance arteries of spontaneously diabetic rats

1. Previous studies have shown that endothelium-dependent relaxation in the aorta of spontaneously diabetic bio bred rats (BB) is impaired. 2. We have investigated noradrenaline (NA) contractility, endothelium-dependent acetylcholine (ACh) and bradykinin (BK) relaxation, and endothelium-independent sodium nitroprusside (SNP) relaxation in mesenteric resistance arteries of recent onset BB rats and established insulin treated BB rats, compared to their age-matched non diabetic controls. 3. There was no significant difference in the maximum contractile response or sensitivity to noradrenaline in either of the diabetic groups compared to their age-matched controls. 4. Incubation with the nitric oxide synthetase inhibitor NG-nitro-L-arginine (L-NOARG) resulted in a significant increase in maximum contractile response to noradrenaline in the recent onset age-matched control group (P < 0.05). Analysis of the whole dose-response curve (using ANOVA for repeated measures with paired t test) showed a significant left-ward shift following the addition of L-NOARG (P < 0.001). A similar but less marked shift (P < 0.01) was evident in vessels from recent onset diabetics. An overall shift in both sensitivity and maximum response was also evident in the age-matched non diabetic controls of the insulin-treated group (P < 0.05). However, by contrast, there was no significant change in sensitivity in the insulin-treated diabetic rats. 5. ACh-induced endothelium-dependent relaxation was significantly impaired in the recent onset diabetic rats compared to their age-matched controls (47 +/- 11% versus 92 +/- 2%, P < 0.05, n = 6), and in the insulin treated diabetic rats (34 +/- 5% versus 75 +/- 6%, P < 0.05, n = 6). The relaxation responses to BK also were significantly impaired in the diabetic rats compared to their age-matched controls (recent onset: 20 +/- 3% versus 72 +/- 7%, P < 0.05, n = 6; insulin treated: 12 +/- 9% versus 68 +/- 7%, P < 0.05, n = 7). 6. Incubation with either the nitric oxide synthetase substrate, U-arginine, or the free radical scavenging enzyme superoxide dismutase (150 mu ml-1) failed to improve the attenuated response of acetylcholine-induced relaxation in the diabetic vessels. 7. Endothelium-dependent relaxation mediated by ACh and BK was significantly attenuated in both the diabetic and control vessels after incubation with L-NOARG. 8. Pretreatment with a cyclo-oxygenase inhibitor, indomethacin, significantly enhanced the relaxation to ACh in both the recent onset and insulin treated diabetic rats (42 +/- 10%, n = 7 versus 64 +/- 7%, n = 7, P < 0.05, and 40 +/- 5%, n = 7 versus 65 +/- 9%, n = 6, P < 0.05). 9. Following endothelium removal, there was a marked impairment in endothelium-dependent relaxation responses to ACh and BK in both the diabetic and control vessels. 10. Incubation with the thromboxane A2 receptor antagonist SQ29548, did not significantly improve the ACh endothelium-dependent relaxation response in the diabetic vessels. 11. Endothelium-independent relaxation to sodium nitroprusside was significantly impaired in the first group of diabetic vessels studied; however, subsequent studies showed no impairment of the sodium nitroprusside response in the diabetic vessels. 12. In conclusion, the ability of the endothelium to regulate vascular contractility is reduced in recent onset diabetic vessels, and significantly impaired in established insulin treated diabetics. Relaxation to the endothelium-dependent vasodilators ACh and BK was impaired in both the recent onset and the established insulin treated diabetics, and the ACh response was significantly improved following pretreatment with indomethacin, suggesting a role for a cyclo-oxygenase-derived vasoconstrictor. Preliminary studies with a thromboxane A2, receptor antagonist, SQ29548 did not significantly improve the impaired relaxation to ACh, indicating that the vasoconstrictor prostanoid is not thromboxane A2.     

Effect of melatonin in the rat tail artery: role of K+ channels and endothelial factors

1. The role of endothelial factors and potassium channels in the action of the pineal hormone melatonin to potentiate vasoconstrictor responses was investigated in the isolated perfused tail artery of the rat. 2. Melatonin (100 nM) potentiated contractile responses to both adrenergic nerve stimulation and alpha1-adrenoceptor stimulation by phenylephrine. After removal of the endothelium, melatonin no longer caused potentiation. 3. The potentiating effect of melatonin was also lost when nitric oxide synthase was inhibited with L-NAME (10 nM). Thus potentiating effects depend on the presence of nitric oxide released by the endothelium. However, melatonin did not affect relaxation responses to acetylcholine in endothelium-intact arteries, nor did melatonin modulate relaxing responses to sodium nitroprusside in endothelium-denuded arteries. While melatonin does not appear to modulate agonist-induced release of nitric oxide nor its effect, melatonin may modulate nitric oxide production induced by flow and shear stress. 4. When the Ca2+-activated K+ channel opener, NS 1619 (10 microM), was present, potentiating effects of melatonin were restored in endothelium-denuded vessels. However, addition of the opener of ATP-sensitive K+ channels, cromakalim (3 microM), did not have the same restorative effect. Furthermore, addition of a blocker of Ca2+-activated K+ channels, tetraethylammonium (1 mM), significantly attenuated potentiating effects of melatonin. These findings support the hypothesis that melatonin inhibits the activity of large conductance Ca2+-activated K+ channels to produce its potentiating effects. 5. Thus in the rat perfused tail artery, potentiation of constriction by melatonin depends on the activity of both endothelial factors and Ca2+-activated K+ channels. Our findings suggest that melatonin inhibits endothelial K+ channels to decrease flow-induced release of nitric oxide as well as block smooth muscle K+ channels to enhance vascular tone.     

Anomalous origin of the right pulmonary artery from the ascending aorta--a report of three operative cases

Three patients with anomalous origin of the right pulmonary artery from the ascending aorta were reported. Case 1: A 33-day-old premature infant (body weight 984 g) with the right pulmonary artery arising from the ascending aorta (RAPAA) and the patent ductus arteriosus (PDA). Banding of the right pulmonary artery (RPAB) and ligation of PDA were performed as a palliative operation. AT 3-month-old (BW 2,200 g), division and direct anastomosis of the anomalous vessel to the main pulmonary trunk was done as a radical operation under hypothermic cardiopulmonary bypass (CPB). Case 2: A 16-day-old infant with RAPAA and PDA. Division and direct anastomosis of the anomalous vessel to the main pulmonary trunk and ligation of PDA were performed as a radical operation under hypothermic CPB. Case 3: A 74-day-old infant with RAPAA and Ebstein's anomaly. RPAB was performed as a first palliative operation and left Blalock-Taussig shunt as a second operation. Glenn operation is scheduled as third operation prior to Fontan type operation.     

Solitary pulmonary nodule due to Leishmania in a patient with AIDS

BACKGROUND: Nitric oxide is an endothelium-derived vasodilator. Cardiopulmonary bypass may induce transient pulmonary endothelial dysfunction with decreased nitric oxide release that contributes to postoperative pulmonary hypertension and lung injury. Exhaled nitric oxide levels may reflect, in part, endogenous production from the pulmonary vascular endothelium. METHODS: We measured exhaled nitric oxide levels before and 30 minutes after cardiopulmonary bypass in 30 children with acyanotic congenital heart disease and left-to-right intracardiac shunts undergoing repair. RESULTS: Exhaled nitric oxide levels decreased by 27.6%+/-5.6% from 7+/-0.8 to 4.4+/-0.5 ppb (p < 0.05) 30 minutes after cardiopulmonary bypass despite a reduction in hemoglobin concentration. CONCLUSIONS: The decrease in exhaled nitric oxide levels suggests reduced nitric oxide synthesis as a result of pulmonary vascular endothelial or lung epithelial injury. This may explain the efficacy of inhaled nitric oxide in the treatment of postoperative pulmonary hypertension. Furthermore, strategies aimed at minimizing endothelial dysfunction and augmenting nitric oxide production during cardiopulmonary bypass may decrease the incidence of postoperative pulmonary hypertension. Exhaled nitric oxide levels may be useful to monitor both cardiopulmonary bypass-induced endothelial injury and the effect of strategies aimed at minimizing such injury.     

Phacotrabeculectomy with "smile" incision, punch, and single releasable suture

A 66-year-old female had ischemic heart disease due to left main lesion complicated with calcified ascending aorta, right pelvic carcinoma and liver cirrhosis. The combined operations with coronary artery bypass by left internal thoracic artery under the hypothermic ventricular fibrillation with cardiopulmonary bypass and right nephrectomy were performed successfully. Postoperatively Treadmill exercise test and scintigram revealed no ischemihc change. She is doing well. The aortocoronary bypass to left anterior descending artery using a left internal thoracic artery under hypothermic ventricular fibrillation with cardiopulmonary bypass might be one of surgical options for high risk patient.     

In vitro characterization of tachykinin NK2-receptors modulating motor responses of human colonic muscle strips

BACKGROUND: Endothelium plays a key role in graft patency. My colleagues and I have developed a verapamil+nitroglycerin solution (balanced to pH 7.4) to prepare the radial artery without mechanical distention or dilation and have reported the efficacy of its antispastic action. This study was designed to investigate whether using this solution as part of the University of Hong Kong protocol to prepare the radial artery is more efficacious than papaverine solution in preserving endothelial function. METHODS: Ring segments of the radial artery taken from 25 patients undergoing coronary artery bypass grafting were studied in organ chambers. The endothelium-dependent relaxation, as the index of endothelial function, was examined by two mechanisms-receptor-mediated relaxation (by acetylcholine) and non-receptor-mediated relaxation (by calcium ionophore A23187) in U46619-induced contraction (10 nmol/L). RESULTS: In the relaxation induced by either acetylcholine (27.3% +/- 5.0% [n = 7] vs 23.9% +/- 3.9% [n = 6],p = 0.6) or A23187 (62.9% +/- 6.0% [n = 13] vs 62.3% +/- 8.4% [n = 6],p = 0.96), there was no significant difference between the control radial arteries and those treated with the verapamil+nitroglycerin solution. In the papaverine-treated rings, acetylcholine-mediated relaxation was abolished (3.3% +/- 2.6% vs 23.9% +/- 3.9%,p < 0.001) and A23187-mediated relaxation was significantly reduced (39.7% +/- 5.2% vs 62.3% +/- 8.4%, p = 0.02) compared with verapamil+nitroglycerin treatment. CONCLUSION: Use of verapamil+nitroglycerin solution to prepare the radial artery maximally preserves endothelial function. In contrast, papaverine impairs this function. Verapamil+nitroglycerin solution may be effectively and safely used to prepare the radial artery for coronary artery bypass grafting.